1. Field of the Invention
The present invention relates to novel pharmaceutical compositions containing steroid nitrate ester derivatives, and to their use treating inflammatory diseases.
2. Related Art
Steroids, specifically of the glucocorticoid class of molecules, are known to possess anti-inflammatory and immunomodulatory activities and are commonly utilized for the treatment of numerous autoimmune and inflammatory diseases. However, their beneficial effects are often slow to develop and accompanied by many dose-limiting side-effects. Nitric oxide donors, such as nitroglycerin, have also been utilized as pharmaceutical agents with prominent beneficial effects on the cardiovascular system. Many of the biological actions of nitric oxide potentially counteract the side-effects of the glucocorticoids and may enhance their therapeutic actions. The present invention relates to novel steroid nitrate ester derivatives that possess the combined biological properties of glucocorticoids and nitric oxide donors in a single molecule. These molecules have an advantage over currently utilized glucocorticoids in that they rapidly elicit beneficial pharmacological effects, such as bronchial relaxation, through the release of nitric oxide. It is intended that these novel molecules be utilized for therapy, in particular their use as anti-inflammatory and immunosuppressive drugs for the treatment of rheumatic diseases, immunological disorders, skin disorders, inflammation, transplant rejection, cancer, osteoporosis, rhinitis and asthma with less side-effects.
Glucocorticoids are commonly utilized for the pharmacologic treatment of inflammation and undesirable immune system reactions. These steroids have the capacity to prevent or suppress the development of inflammation resulting from a number of different injurious agents including infectious, immunological, chemical, mechanical, and radiation. Glucocorticoids are also effective in the treatment of immune system disorders including autoimmune diseases such as rheumatoid arthritis and lupus, and transplant rejection. However, the therapeutic applications of these steroids are somewhat limited due to toxicity and side-effects. The major side effects of the glucocorticoids are hypertension, peptic ulcers, increased susceptibility to infections, osteoporosis, hyperglycemia, and vascular occlusion.
It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amylnitrite ester, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme nitric oxide synthase. The NO released by the constitutive enzyme acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms.
NO is the endogenous stimulator of the soluble guanylate cyclase and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews, 43, 109-142 (1991). Furthermore, NO has been shown to possess anti-thrombotic (see Moncada et al. Journal of Cardiovascular Pharmacology 17, S25 (1991), Byrne et al., World Patent application WO09403421-A2 and Schonafinger et al., German Patent application DE4223800-A1), bronchorelaxant (Persson et al. European Journal of Pharmacology, 249, R7-R8 (1993), anti inflammatory, microbialcidal (Alspaugh and Granaer, Infection and Immunity 59, 2291-2296 (1991) and gastroprotective (see Wallace et al. European Journal of Pharmacology, 257, 249-255 (1994) effects in animal models. In addition, nitric oxide has been suggested to be effective against the loss of bone in in vitro models of osteoporosis (MacIntyre et al. Proc.Natl.Acad.Sci.USA 88, 2936-2940 (1991) and in inhibiting angiogenesis, tumor growth and metastasis in in vivo animal models (Pipili-Synetos et al. British Journal of Pharmacology, 116, 1829-1834 (1995).
The properties noted above make nitric oxide an ideal agent to enhance the actions of corticosteroids in the treatment of various diseases mentioned earlier by both increasing their biological effects as well as by reducing their side effects.